Abstract Bruton?s Tyrosine Kinase (BTK) is a clinically proven target to attenuate B-cell receptor (BCR) signaling in B-cell malignancies, including mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL). Ibrutinib, a first-in-class, once-daily, oral covalent BTK inhibitor was approved by the FDA to treat relapsed/refractory MCL in 2013 based on the multiple-center Phase II clinical trial led by Dr. Michael Wang (multi-PI on this application). Although ibrutinib has been successful in treating MCL and CLL, acquired resistance arises quickly, mostly through mutations in the BTK kinase domain to significantly reduce ibrutinib efficacy in CLL and the activation of alternative survival pathways in MCL. Additionally, disrupting kinase function of BTK using kinase inhibitors is the only currently available therapeutic intervention on this well-validated target. However, BTK can also enhance antigen receptor-induced calcium influx in a kinase-independent manner, while a kinase inactive BTK mutant can partially rescue B cell development of BTK-null B cells in mice. In this project, we will develop a small molecule therapeutic agent that can efficiently inhibit and degrade BTK in cells irrespective of BTK mutation status to abolish both BTK kinase and non-kinase activities completely. In our preliminary studies, we developed RC-1 as the first reversible covalent chemistry-based BTK degrader. Based on our highly promising preliminary studies, extensive expertise in drug development, and clinical expertise in MCL and CLL, we hypothesize that further optimization of RC-1 will lead to a next-generation targeted therapy for MCL, CLL and other B-cell malignances and significantly improve treatment outcomes. To achieve this goal, we have assembled a highly motivated team with complementary expertise. Dr. J. Wang is an expert in chemical biology and drug discovery. His previous work led to the development of the first-in-class inhibitor for steroid receptor coactivators, which is under commercialization. His laboratory has established the full pipeline for drug discovery, including organic synthesis, in vitro assays, ADMET profiling and preclinical efficacy testing. Dr. M. Wang (MD Anderson) and Dr. Woyach (Ohio State) are leading physician scientists in lymphoma research, specializing in the BTK signaling pathway. Dr. M Wang?s clinical studies led to the FDA approval of two BTK inhibitors, ibrutinib and acalabrutinib. Dr. Woyach is a leader in ibrutinib-resistant mechanisms. In this project, we will further optimize BTK degraders with drug-like properties and test the therapeutic efficacies in MCL and CLL mouse models. In our and others? studies, BTK degraders can be more potent than inhibitors in certain B cell malignancies. This novel mechanism of action for BTK targeting has never been explored in the clinic. We expect that successful completion of this project will make a significant impact on the treatments of B-cell malignancies.